Lumbar disc (LD) herniation and aging are prevalent conditions that can result in substantial morbidity. This study aimed to clarify the mechanisms connecting the LD aging and herniation, particularly focusing on cellular senescence and molecular alterations in the nucleus pulposus (NP). We performed a detailed analysis of NP samples from a diverse cohort, including individuals of varying ages and those with diagnosed LD herniation. Our methodology combined histological assessments with single-nucleus RNA sequencing to identify phenotypic and molecular changes related to NP aging and herniation. We discovered that cellular senescence and a decrease in nucleus pulposus progenitor cells (NPPCs) are central to both processes. Additionally, we found an age-related increase in NFAT1 expression that promotes NPPC senescence and contributes to both aging and herniation of LD. This research offers fresh insights into LD aging and its associated pathologies, potentially guiding the development of new therapeutic strategies to target the root causes of LD herniation and aging.
Intervertebral Disc Displacement/metabolism* ; Humans ; Aging/pathology* ; Nucleus Pulposus/pathology* ; Male ; Female ; Transcriptome ; Middle Aged ; Lumbar Vertebrae/pathology* ; Adult ; Cellular Senescence ; Stem Cells/pathology* ; Aged ; Intervertebral Disc Degeneration/metabolism*

ObjectiveTo investigate the incidence rate of sarcopenia in patients with Wilson’s disease （WD）-related liver cirrhosis， as well as the risk factors for sarcopenia and their impact on clinical outcomes. MethodsA total of 140 patients with WD-related liver cirrhosis who were treated in The First Affiliated Hospital of Anhui University of Chinese Medicine from January 2019 to June 2020， and according to the third lumbar skeletal muscle mass index （L3 SMI）， the patients were divided into sarcopenia group and non-sarcopenia group. Nutritional risk screening， anthropometric measurements， and blood biochemical tests were performed for the patients to identify the influencing factors for sarcopenia. The patients were followed up for 36 — 48 months， and survival status and complications were compared between the two groups. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the chi-square test and the Mann-Whitney U rank sum test were used for comparison of categorical data between two groups. A binary Logistic regression analysis was used to investigate the influencing factors for sarcopenia， and univariate and multivariate Cox regression analyses were used to investigate the risk factors for the prognosis of patients with WD-related liver cirrhosis. The Kaplan-Meier survival curve was plotted， and the Log-rank test was used for comparison between groups. ResultsAmong the 140 patients with WD-related liver cirrhosis， 53 （37.9%） developed sarcopenia， with significantly lower body mass index （BMI） and L3 SMI than the patients without sarcopenia （t=10.550 and 3.982， both P<0.001）. The multivariate Logistic regression analysis showed that age （odds ratio ［OR］=2.243， 95% confidence interval ［CI］： 1.196 — 4.208， P=0.012）， sex （OR=0.450， 95%CI： 0.232 — 0.872， P=0.018）， BMI （OR=0.126， 95%CI： 0.089 — 0.294， P<0.001）， and hepatic encephalopathy （OR=8.367， 95%CI： 2.423 — 28.897， P<0.001） were the main influencing factors for sarcopenia in patients with WD-related liver cirrhosis. Compared with the non-sarcopenia group， the sarcopenia group had significantly higher mortality rate （χ²=6.158， P=0.019） and significantly higher incidence rates of infection （χ²=8.008， P=0.040）， recurrent abdominal/pleural efflux （χ²=17.742， P<0.001）， and hepatic encephalopathy （χ²=4.338， P=0.039）. The multivariate Cox regression analysis showed that sarcopenia （hazard ratio ［HR］=4.685， P=0.002） and hepatic encephalopathy （HR=19.156， P<0.001） were independent risk factors for death in patients with WD-related liver cirrhosis. The Kaplan-Meier survival curve analysis showed a significant reduction in survival rate in the patients with sarcopenia （P=0.003）. ConclusionSarcopenia is one of the manifestations of malnutrition in patients with WD-related liver cirrhosis， which increases the risk of mortality and other complications and has an adverse effect on prognosis. There is an increased risk of sarcopenia in male patients or patients with hepatic encephalopathy， a lower level of BMI or an older age.

Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
Humans ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Transcription Factors/metabolism* ; Gene Expression Regulation ; Hypoxia/metabolism* ; Cell Hypoxia/physiology*

Objective:To investigate the clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation (CAED).Methods:Eight cases of CAED diagnosed at the Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China from January 2017 to August 2023 were collected. The histopathological, immunohistochemical, molecular and prognostic features of 8 CAED cases were analyzed. The relevant studies were also reviewed.Results:Among the eight patients, there were six males and two females, with an average age of 58 years (range: 29-77 years, median age: 61.5 years). Preoperative serum alpha-fetoprotein levels were elevated in five patients (14.0-286.6 μg/L). Four tumors were located in the colon, and four tumors in the rectum. Two patients were clinically staged as advanced stage (stage Ⅳ), and distant metastasis occurred at the initial diagnosis (one case had liver metastasis, and the other had lung, bone and multiple lymph nodes metastases). Six patients were clinically staged as locally-advanced stage (Stage Ⅱ-Ⅲ). Three of them developed distant metastases after surgery (one case had liver metastasis, one case had lung metastasis, and one case had peritoneal metastasis). Additionally, two patients died at 9 months and 24 months after surgery, respectively. The tumors were composed of various proportions of adenocarcinoma components with enteroblastic differentiation (30%-100%) and classical tubular adenocarcinoma components. The component with enteroblastic differentiation exhibited morphology similar to embryonic intestinal epithelium: cuboidal or columnar tumor cells arranged in tubular, papillary, cribriform, or solid nest patterns, with clear cytoplasm. Immunohistochemical studies showed that tumor cells expressed at least one oncofetal protein (SALL4, Glypican-3, and AFP). In addition, focal squamous differentiation was observed in 3 cases (3/8). Compared to the primary tumor, both CAED and squamous differentiation components were increased in the metastatic tumors. Based on the sequencing results of KRAS, NRAS and BRAF of the primary and/or metastatic tumors, 5 cases were wild-type, while KRAS exon 2 (G13D) mutations were identified in 2 cases.Conclusions:CAED is a rare colorectal malignancy with a dismal prognosis. Accurate pathological diagnosis is prognostically valuable. The histological features of enteroblastic differentiation, elevated serum AFP levels, and the expression of oncofetal proteins play an important role in the tumor diagnosis.

Objective:To investigate the effect of preoperative radiotherapy on postoperative recurrence in central hepatocellular carcinoma patients treated by hepatectomy.Methods:A retrospective cohort study was conducted. Clinicopathological data of 142 patients with central hepatocellular carcinoma who underwent surgical treatment at the Cancer Hospital of Chinese Academy of Medical Sciences and Peking Union Medical College from January 2016 to January 2019 were retrospectively collected. According to whether they received preoperative radiotherapy or not, the patients were divided into preoperative radiotherapy group (30 cases) and surgery-only group (112 cases). The main observation indexes were recurrence-free survival (RFS), intraoperative bleeding amount, operation time and the occurrence of postoperative complications. Kaplan-Meier method was used for survival analysis, and log-rank test was used for intergroup comparisons; the differences between the two groups for each factor were evaluated by standardized mean difference (SMD); Cox proportional hazards model was used to analyze the influencing factors of RFS in central hepatocellular carcinoma patients with hepatectomy. Propensity score matching (PSM), regression model-adjusted propensity score (CAPS) and inverse probability of treatment weighting (IPTW) methods were used to investigate the relationship between exposure factors and confounding variables and RFS. Sensitivity analysis was performed using E-value to assess the potential impact of unmeasured confounders on outcomes.Results:Men comprised 96.7% (29/30) and 87.5% (98/112) of the preoperative radiotherapy and surgery-only groups, with ages of (55±10) years old and (54±12) years old, respectively. Before matching by the PSM method, there were differences in gender, proportion of patients with hepatitis C, alanine aminotransferase, serum albumin, alpha-fetoprotein, satellite nodules by postoperative pathology, and number of tumors between the two groups (all SMD > 0.1). A total of 26 pairs of patients were successfully matched, and there was no difference in baseline characteristics between the preoperative radiotherapy group and the surgery-only group after matching (all SMD < 0.1). Univariate Cox regression analysis showed that preoperative radiotherapy, number of tumors, maximum diameter of tumor, and satellite nodules by postoperative pathology were the influencing factors of RFS (all P < 0.05); multivariate Cox regression analysis showed that preoperative radiotherapy was an independent protective factor of RFS in central hepatocellular carcinoma patients with hepatectomy ( HR = 0.55, 95% CI: 0.31-0.97, P = 0.038), and maximum diameter of tumor ( HR = 1.08, 95% CI: 1.02-1.15, P = 0.005) and satellite nodules by postoperative pathology ( HR = 1.97, 95% CI: 1.21-3.19, P = 0.006) were independent risk factors of RFS. Preoperative radiotherapy was associated with superior RFS in patients with central hepatocellular carcinoma (PSM, HR = 0.41, 95% CI: 0.20-0.86, P = 0.018; CAPS, HR = 0.42, 95% CI: 0.20-0.87, P = 0.019; IPTW, HR = 0.41, 95% CI: 0.22-0.76, P = 0.005). Before matching, the 1-, 3-, and 5-year postoperative RFS rates in the preoperative radiotherapy group were 77%, 56% and 45%, respectively, and the surgery-only group were 48%, 32% and 28%, respectively. RFS in the preoperative radiotherapy group was superior to that in the surgery-only group before and after matching ( χ2 = 5.65, P = 0.017; χ2 = 6.00, P = 0.014). The E-value for unmeasured confounders altering the conclusions was 2.39, suggesting reliable and stable results. After matching, intraoperative bleeding [ M ( Q1, Q3)] for patients in the preoperative radiotherapy group and the surgery-only group was 300 ml (125 ml, 600 ml) and 400 ml (200 ml, 600 ml), respectively ( U = 0.51, P = 0.611), and the proportions of patients with the operation time >180 min were 92.3% (24/26) and 84.6% (22/ 26), respectively ( χ2 = 0.75, P = 0.385), and the rates of mild postoperative complications were 100.0% (26/26) and 92.3% (24/26), respectively ( χ2 = 2.08, P = 0.149), the differences were not statistically significant. Conclusions:Preoperative radiotherapy for hepatectomy in patients with central hepatocellular carcinoma is safe and effective, and has the advantage of reducing postoperative recurrence.

Small molecule drug screening technology is continuously evolving and expanding along with drug discovery,and the innovation in drug screening technology can improve the research and development efficiency and success rate,shorten the cycle time,and reduce the cost.From traditional screening technologies based on known active compounds and high-throughput screening(HTS)to new technologies such as structure-based drug discovery(SBDD),fragment-based drug discovery(FBDD),DNA encoded compound library(DEL)and proteolysis targeting chimeras(PROTAC),small molecule drug screening technologies are continuously broadening the market potential for small molecule drugs.This article will provide an overview of the current status of small molecule drug screening technology,systematically review each technique along with their advantages and disadvantages,and offer essential insights for the development of new small molecule drug screening technologies.

Objective:To compare the therapeutic effects of modified plantar skin grafting and thigh skin grafting on the deep burn wounds of the back and buttocks.Methods:A retrospective cohort study was conducted to analyze the clinical data of 30 patients with deep burn wounds on their back and buttocks who were admitted to the 910th Hospital of Joint Logistic Support Force of PLA from January 2021 to April 2023, including 26 males and 4 females, aged 21-72 years [(49.9±14.0)years]. The total burn size was 50%-97% of the total body surface area (TBSA), with the third-degree burn on the back and buttocks 6%-16% TBSA. The burn wounds on the back and buttocks were repaired using plantar skin grafts alone, thigh skin grafts alone or plantar skin grafts combined with the grafts from other body parts. The patients were grouped according to the skin graft donor sites and the times of harvesting skin grafts: there were 20 patients undergone plantar skin grafting including 10 patient with plantar skin graft harvested once (group of plantar skin graft harvested once) and 10 patients with plantar skin graft harvested twice or three times (group of plantar skin graft harvested more than once), and 10 patients undergone thigh skin grafting harvested once (group of thigh skin graft harvested once). The areas of plantar skin grafts harvested at the last time and the wound areas on the back and butts that could be repaired each time were calculated. After the last harvest, the thickness of the stratum corneum, 7-day survival rate of the skin grafts, proportion of 3-month residual wound area in the skin graft area, healing time of the donor sites, and 6-month Vancouver Scar Scale (VSS) scores of the donor sites in the group of plantar skin graft harvested once were compared with those in the group of thigh skin graft harvested once and the group of plantar skin graft harvested more than once. The appearance and texture of the skin graft, patients′ walking patterns and complications were observed at 6 months after the last skin harvest.Results:All the patients were followed up for 6-18 months [(7.8±1.6)months]. In the 20 patients with plantar skin grafts harvested, the areas of skin grafts harvested at the last time were 2.5%-4.5% TBSA [(3.4±0.6)% TBSA] and the wound areas that could be repaired each time were 3%-8% TBSA [(5.5±1.5)% TBSA]. After the last harvest, the thickness of the stratum corneum in the group of plantar skin graft harvested once was (190.4±8.9)μm, which was significantly thicker than that in the group of thigh skin graft harvested once [(50.0±6.6)μm] and that in the group of plantar skin graft harvested more than once [(166.8±21.9)μm] ( P<0.01); the 7-day survival rate of the skin grafts, proportion of 3-month residual wound area in the skin graft area, healing time of the donor sites, and 6-month VSS scores of the donor sites were (93.6±2.3)%, 2.0 (0.1, 3.5)%, (9.9±1.8)days and (1.7±0.7)points in the group of plantar skin graft harvested once, (78.0±6.6)%, 5.3 (4.0, 5.8)%, (14.0±1.4)days and (4.9±2.3)points in the group of thigh skin graft harvested once, and (93.4±2.6) %, 2.0 (0.1, 3.8)%, (10.0±1.2)days and (1.8±0.8)points in the group of plantar skin graft harvested more than once. The group of plantar skin graft harvested once showed a significant increase in the 7-day survival rate and a significant decrease in the proportion of 3-month residual wound area in the skin graft area, healing time of the donor sites, and 6-month VSS scores of the donor sites in comparison with the group of thigh skin graft harvested once ( P<0.05 or 0.01), while there were no significant differences in above mentioned indices between the group of plantar skin graft harvested once and the group of plantar skin graft harvested more than once ( P>0.05). At 6 months after the last skin harvest, the skin graft areas on the back and buttocks were flat, hard and firm and all the patients in the three groups could walk normally, with no complications such as severe itching, pain or folliculitis in the skin graft area. Conclusions:In the treatment of burn wounds on the back and buttocks, compared with thigh skin grafting, modified plantar skin grafting has advantages of thicker stratum corneum, better wear resistance and pressure resistance in the skin graft areas, a higher survival rate of skin grafts, rapid healing, mild scar, and undisturbed walking pattern after surgery and no common complications. Moreover, skin grafts can be harvested repeatedly from the donor sites, with no impact on the therapeutic effects.

Objective:To investigate the relationship between the number of removed lymph nodes(RLN)and patient prognosis during radical surgery for extensive cervical cancer(CC).Methods:Clinical data of 21416 pa-tients with CC who underwent radical hysterectomy between January 1,2004 to August 31,2018 in the Chinese Cervical Cancer Clinical Study was retrospectively reviewed.Restricted cubic spline(RCS)was used to analyze the dose-response relationship between the number of RLN and prognosis.The patients were divided into three groups according to the RCS and RLN number:1-17 group(8733 cases),18-26 group(8189 cases),and≥ 27 group(4494 cases).Kaplan-Meier survival analysis and Log-Rank tests were used to compare the OS rates and DFS rates between groups at 3 and 5 years.Multivariate Cox proportional hazards model was used to analyze the prognostic mortality risk.Results:① RCS results showed a U-shaped nonlinear dose-response relationship be-tween the number of RLN and prognosis(P＜0.01).When the number of RLN was less than 26,the risk of death decreased as the number of RLN increased,and the risk was lowest when the number of RLN was 26.②There were statistically significant differences(P＜0.05)in age,histological type,tumor diameter,nerve invasion,uterine invasion,vaso-lymph node space invasion,cervical invasion,number of lymph node metastasis,whether preopera-tive adjuvant therapy was received,postoperative adjuvant therapy,and whether postoperative adjuvant therapy was standardized among the 3 groups(P＜0.05).③Kaplan-Meier survival curve analysis showed that the 5-year OS of the 1-17 group,18-26 group,and ≥ 27 group were 90.23％,92.28％,and 91.61％,respectively,and the 5-year DFS were 85.32％,87.90％,and 87.18％,respectively.The differences between the three groups were sta-tistically significant(P＜0.01).④The results of multivariate Cox regression analysis showed that RLN number in the range of 1-17 was a significant risk factor for the 3-and 5-year OS and DFS,when compared to the 18-26 RLN group(HR＞1,P＜0.05).Conclusions:RLN number may be one of the prognostic indicators of CC.When the number of RLNs is between 18-26,the prognosis of the patient may be better.The number of RLN in the range of 1-17 may increase the risk of recurrence or death in CC patients.